Benzodiazepines
Brain-Disabling Effects Of Benzodiazepines
By Peter R. Breggin, M.D.
From Brain-Disabling Treatments in Psychiatry
This is the first page of a two page article.
The benzodiazepines (BZs) have for several decades been recognized in the literature and clinical practice for their capacity to cause mental and behavioral abnormalities.
Xanax (alprazolam), and to an even greater extent, Halcion (triazolam), have a significantly different profile from other benzodiazepines due to their greater capacity to bind to receptors and their shorter half-life.
Halcion's very short half-life led to the hope that it would make a particularly good sleeping medication but it has proven especially dangerous.
The brain-disabling or toxic effects of the Bzs in general can be divided into several somewhat overlapping categories:
(1) The primary clinical effect of inducing sedation (tranquility) or hypnosis (sleep), which is indistinguishable from a toxic effect except in degree;
(2) Cognitive dysfunction, ranging from short-term memory impairment and confusion to delirium;
(3) Disinhibition and other behavioral aberrations-- including extreme agitation, psychosis, paranoia, and depression, sometimes with violence toward self or others;
(4) Withdrawal, in which the individual experiences a continuum of symptoms from anxiety and insomnia after routine use to psychosis and seizures after the abrupt termination of long-term, larger doses;
(5) Rebound, an aspect of withdrawal, in which the individual develops anxiety, insomnia, or other serious emotional reactions that are more intense than before drug treatment began. Withdrawal can take place between doses during the routine administration of Bzs, especially the short-acting ones.
(6) Habituation and addiction, along a continuum from feeling dependent on the drug to compulsively organizing one's behavior in a self-destructive manner around obtaining large amounts of the agent.
The Mechanism of Brain-Disability Neurophysiological studies show that the BZs potentiate the neuronal inhibition that is mediated by gamma-aminobutyric acid (GABA).
In doses used clinically, this results in a generalized suppression of both spontaneous and evoked electrical activity of the large neurons throughout all regions of the brain and spinal cord (Ballenger, 1995).
The binding of BZs to the GABA receptors is most intense in the cerebral cortex. Some BZs, such as Xanax and Halcion, bind especially tightly, increasing their tendency to produce more intense sedation and hypnosis, and also more severe cognitive deficits, behavioral abnormalities, rebound, and withdrawal.
Some advocates of the BZs have argued for a specific anti-anxiety effect separate from the general sedative effect, but there's no substantial evidence for this.
Rall (1990) concludes: The question whether the so-called antianxiety effects of the benzodiazepines are the same or different from the sedative and hypnotic effects has not been resolved.
People who use BZs to calm their anxiety will frequently use alcohol and other sedatives interchangeably for the same purpose, either in combination or at different times.
As they switch from drug to drug, they tend to find little or no difference in the anti-anxiety effect. This confirms the brain-disabling principle that BZs have no specificity for anxiety in comparison to other sedative/hypnotic agents. The Mechanism for Producing Behavioral Abnormalities.
There are at least two probable causes for the abnormal behavior produced by BZs. One mechanism is direct intoxication, resulting in impaired executive and cognitive function, including reduced judgment and impulse control.
Fogel and Stone (1992, p. 341) observe Benzodiazepines, given to reduce arousal or possibly to treat a hypomanic state, may aggravate impulsive behavior by impairing the inhibition mechanism of the frontal lobes. Barbiturates may have similar effects.
Especially in regard to the BZs, a second mechanism, rebound, has been demonstrated, and is a probable cause of many more severe reactions.
Rebound or discontinuation symptoms occur when the BZs are withdrawn or when they begin to lose their effectiveness (American Psychiatric Association, 1990). As the BZ disappears from the GABA receptor sites, the receptors may have become down-regulated (less sensitive).
Or there may be a reduction in GABA itself in response to the drugs, once again leaving the GABA system relatively inactive. Without the inhibiting effects of the GABA system, the disinhibited brain over-reacts.
The American Psychiatric Association (1990) task force report, Benzodiazepine Dependence, Toxicity, and Abuse, theorized that discontinuation symptoms arise from the abrupt withdrawal of BZs from their receptor sites. Before GABA can retake these positions, there is an acute reduction of GABA, and a loss of GABA inhibitory tone.
BZ disinhibition differs in some ways from alcohol disinhibition. It can occur without a noticeable sedative intoxication, such as slurred speech, lack of coordination, or impaired consciousness. Furthermore, the BZs are prescribed by a physician, often without providing the patient a warning about possible disinhibition.
Unlike the experienced alcohol user, the trusting BZ user has little reason to anticipate losing control. Expecting to be helped, and not harmed, by the drug, the patient is less able to understand or manage potentially overwhelming feelings of anger or violence, or other untoward emotional responses.
Also unlike alcohol, some of the worst BZ behavioral reactions occur during withdrawal, or in between doses, adding to the patient's confusion concerning what is happening. At the time, the patient may have little idea what is driving the unfamiliar behavior, and in retrospect it may seem like a fragmented, poorly recalled nightmare.
Adverse Reactions to the BZs as a Group Standard textbooks and reviews spanning more than two decades, as well as a variety of clinical studies, confirm widespread recognition of BZ-induced behavioral abnormalities (DiMascio and Shader, 1970; Kochansky, Salzman, Shader, Harmatz, and Ogeltree, 1975; Shader and DiMascio, 1977; Rosenbaum, Woods, Groves, et al., 1984; Arana and S. Hyman, 1991; Maxmen, 1991; Maxmen and Ward, 1994; Ashton, 1995).
Salzman, Kochansky, Shader, Porrino, Harmatz, and Swett (1974), in a placebo controlled study, showed that volunteers taking chlordiazepoxide became more hostile when confronted with a situation of interpersonal frustration.
In 1988, Dietch and Jennings reviewed the literature concerning reports about disinhibition whose Manifestations range from irritability to increased verbal hostility and frank assault.
They found a variety of studies that demonstrate an increase in feelings of hostility or in verbal hostility. They did not come to a definitive conclusion concerning the existence of the phenomenon, but estimated it was probably rare. Salzman (1992) reviewed the literature.
He too pointed out the controversial nature of BZ-induced violence, but went on to assert, Recent observations, however, have confirmed that hostility can be seen with all benzodiazepines, including alprazolam and clonazepam (citations omitted).
Writing in Goodman and Gilman's The Pharmacological Basis of Therapeutics, Rall (1990) summarized: AAdverse psychological effects: Benzodiazepines may cause paradoxical effects.
Nitrazepam frequently and flurazepam occasionally increase the incidence of nightmares, especially during the first week of use. Flurazepam occasionally causes garrulousness, anxiety, irritability, tachycardia, and sweating.
Euphoria, restlessness, hallucinations, and hypomania behavior have been reported to occur during the use of various benzodiazepines.
Antianxiety benzodiazepines have been reported to release bizarre uninhibited behavior in some users with low levels of anxiety; hostility and rage may occur in others. Paranoia, depression, and suicidal ideation occasionally also accompany the use of these agents.
Rall believed that the incidence of such paradoxical reactions is extremely small. Whether or not that is true, they are extremely hazardous. They are more common in regard to the short-acting Bzs.
The APA task force report on BZs (1990, p. 18) presents a table of discontinuation symptoms. The complete list of frequent discontinuation symptoms includes anxiety, insomnia, restlessness, agitation, irritability, muscle tension.
Among many symptoms that are common but less frequent, it lists depression and nightmares, as well as lethargy. Clinical experience indicates that the combination of anxiety, insomnia, restlessness, agitation, irritability, nightmares, and depression can produce a spectrum of behavioral abnormalities, including suicide and violence.
Adding to the dangers, the task force's complete list of uncommon symptoms includes psychosis, seizures, persistent tinnitus, confusion, paranoid delusions, hallucinations.
The Production of Mania and Rage As the above observations confirm, reactions to Xanax and other benzodiazepines can reach psychotic proportions.
As noted in the 1996 edition of Drug Facts and Comparisons, the BZs in general can cause serious psychiatric problems, including psychosis.
They can disrupt central nervous system function, producing, among other things, disorientation... confusion... delirium.... euphoria... agitation.
A special Precautions section notes Paradoxical reactions, including excitement, stimulation and acute rage and hyperexcited states, anxiety, hallucinations...
Mania, a psychosis, is a special danger in regard to Xanax. The Drug Facts and Comparisons (p. 1440) makes a specific reference to Xanax in this regard, stating that Anger, hostility and episodes of mania and hypomania have been noted with alprazolam.
The fact that mania is a particular risk with Xanax is generally recognized. As another example, Maxmen and Ward's Psychotropic Drug Fast Facts (1995, p. 287) states that manic reactions are Most often reported with alprazolam.
It also states that rage reactions and violent episodes have especially been observed with Xanax and Valium. Yet another example is The Handbook of Psychiatric Drug Therapy (Third edition, 1995, p. 177) by Hyman, Arana, and Rosenbaum.
It singles out Xanax to observe Increased impulsiveness, euphoria, and frank mania have been reported with alprazolam.
Drug Facts and Comparisons, Psychotropic Drug Fast Facts and the Handbook of Psychiatric Drug therapy are intended for ready reference for physicians for the purpose of alerting them to adverse drug reactions they need to be aware of.
That all three indicate that mania and uncontrollable rage are special problems with Xanax confirms my own clinical observations that this medication is more apt than many others to produce these hyper-excited, aggressive psychotic states.
The FDA's Safety Review and Evaluation of Clinical Data by J. Knudsen (1989) for Xanax for panic disorder once again highlighted its tendency to produce mania.
It included a review of Xanax-induced mania from the literature. It described several cases of mania produced in the panic disorder clinical studies and offered two tables described 14 cases of hypomania and one of mania.
Several attacks developed during the first week of treatment at relatively small doses.
The Production of Depression and Suicide As already noted, there are reports in the clinical literature indicating that the BZs can cause depression. Some reviews mention the phenomenon but express skepticism, while nonetheless declaring it should be taken seriously.
Arana and Hyman, for example, stated: ADepression: All benzodiazepines have been associated with the emergence or worsening of depression; whether they were causative or only failed to prevent the depression is unknown.
When depression occurs during the course of benzodiazepine treatment, it is prudent to discontinue the benzodiazepine.
Ashton (1995) observed that benzodiazepines can blunt the emotions in general, producing emotional anesthesia. He reported, Former long-term benzodiazepine users often bitterly regret their lack of emotional response to family events during the period that they were taking the drugs.
Ashton also observed that BZs can precipitate suicide in already depressed patients.
The APA report on BZs (1990), in a discussion of toxicity, also observed: ABenzodiazepines have also been reported to cause or to exacerbate symptoms of depression.
This, too, is not a frequent side effect, although the depressive symptoms may be potentially serious.
Great Britain's Committee on Safety of Medicines (1988) recommended that benzodiazepines should not be used alone to treat depression or anxiety associated with depression. Suicide may be precipitated in such patients.
Due to the action of the BZs on gamma-aminobutyric acid (GABA) receptors, as well as to research in depression, there is growing interest in the role of a GABAergic systems in mood disorders (Kalpana, Musselman, Schatzberg And Nemeroff, 1995; also see Bartholini, Lloyd And Morselli, 1986).
GABA systems have also been associated with the production of anxiety and anger. Cognitive, Emotional and Behavioral Abnormalities Caused by Halcion and Xanax Several studies have demonstrated rebound phenomena the same night or the day following the ingestion of the short-acting BZ, triazolam (Halcion).
In a controlled study, Moon, Ankier and Hayes (1985) found The results support previous reports that early insomnia and an increase in daytime anxiety are problems associated with short acting benzodiazepines, such as triazolam.
De Tullio, Kirking, Zacardelli and Kwee (1989) reviewed the charts of 72 adult male patients taking triazolam for sleep through an ambulatory Veterans Administration clinic. Thirty-nine of the patients were available for telephone interviews.
Most of the patients were elderly (aged 60 or older) and almost all received 0.25 mg. Of the thirty-nine patients interviewed, only 4 reported no adverse effects and 23 experienced more than one. The most common were dizziness, rebound insomnia, and nightmares.
Rebound insomnia was defined as waking during the night or waking too early in the morning, and having trouble falling back to sleep.
As a result of the study, the VA facility modified its policies on triazolam administration: for outpatients on chronic triazolam therapy, a switch to a longer-acting benzodiazepine was instituted with tapering if therapy was not to be continued.
We have already note that the APA task force (1990) on BZs described a variety of symptoms, including depression, anxiety, hostility, and paranoia, and attribute them in part at least to discontinuation or withdrawal. In regard to short-acting BZs, the task force made the following observations:
Abrupt discontinuation of short half-life benzodiazepines leads to rapid drug removal from the blood and brain, rapid uncovering of the receptor site, and relatively rapid onset of post-drug discontinuation syndromes.
Because of the severity of symptoms related to its half-life, short half-life benzodiazepines given for anxiety are frequently implicated in intense discontinuation syndromes.
With very short half-life drugs such as triazolam, rebound symptomatology has actually been described during the period of ingestion, especially when it is given nightly.
Public and professional awareness of the special dangers of Halcion began in 1978.
At that time, C. van der Kroef, a psychiatrist in the Hague, Netherlands, noticed abnormal reactions to Halcion in four of eleven patients he treated with the drug. Here is van der Kroef's description in one of his patients (quoted in Dukes, 1980):
The insomnia improved at once, but psychically she rapidly went downhill. Progressively she became paranoid. Several times she asked me what the hypnotic contained, LSD perhaps? For she felt that she was bordering on psychosis. She felt shut off from the world; it was as if she no longer belonged to society.
Her friends asked her what was happening to her, so strangely was she behaving. After two months I too began to suspect, particularly in light of experience with an earlier patient, that all this might be a consequence of her taking triazolam.
The drug was withdrawn and replaced with nitrazepam. Within a day she felt herself again. The people around her noticed the difference and recognized her old self again. The paranoid traits, the hypermotility urge and the hyperaesthesia disappeared in the course of two days...
M. N. G. Dukes (1980), a physician with considerable regulatory experience, commented on van der Kroef's findings. He observed that all of the BZs, including those used to induce sleep (hypnotics), have been known to produce reactions that are frankly psychotic.
While not common, according to Dukes, virtually every known drug in this class has produced hallucinations, delusions, paranoia, amnesia, delirium, hypomania, almost every conceivable symptoms of psychotic madness.
According to Dukes, all the BZs used for the control of anxiety were also implicated in causing violence:
If one--to begin at an arbitrary point--looks to the literature for evidence that the benzodiazepines can unleash aggression then one will find it.
More than a dozen papers in the literature speak of irritability, defiance, hostility, aggression, rage or a progressive development of hates and dislikes in certain patients treated with benzodiazepine tranquilizers; all those products which are widespread have been incriminated at one time or another.
The phenomenon has been demonstrated in animal studies and it has even been proved possible to show in human volunteers that these drugs can release pent-up hostility, particularly in highly anxious or action-oriented individuals.
Until the advent of Halcion, according to Dukes, the BZs commonly used to induce sleep were not known to cause violence. We shall find his observations confirmed later on by in-house studies at the FDA indicating that Halcion, but not the older hypnotics, Dalmane or Restoril, caused a vastly increased rate of violent activities.
It is, of course, extremely difficult to demonstrate drug-induced behavioral abnormalities in highly selective, short, controlled clinical trials (see chapter 11 for detailed analysis of why this is so).
Nonetheless, several studies have confirmed some of the hazards associated with Halcion. Gardner and Cowdry (1985) found an increase in dyscontrol in borderline patients taking alprazolam in a double-blind, placebo-controlled crossover study.
The dyscontrol included the following: Overdose, severe; Overdose, moderate; Deep neck cuts; Transverse wrist cuts; Tried to break own arm; Threw chair at child; and Arm and heading banging; jumped in front of car.
Gardner and Cowdry pointed out that there are some reports of borderline patients also improving on alprazolam. They concluded, Caution should, however, be exercised, particularly in treating individuals with a substantial history of dyscontrol.
Bayer, Bayer, Pathy and Stoker (1986) conducted a 9 week double-blind controlled study of triazolam and another hypnotic, chlormethiazole, in the elderly with sleep disturbances.
They found daytime withdrawal effects from triazolam but not chlormethiazole. At week three, significantly more triazolam patients were rated as more restless during the day and they also appeared more hostile, less relaxed, more irritable and more anxious.
Patients on triazolam also had more adverse events related to the central nervous system, requiring four of twenty-two patients to withdraw from the study, three of whom recovered after terminating the medication.
One patient felt the tablets were making him nervous. The others individually developed paranoid delusions, increasing confusion and irritability, and irrational, irritable, and uncooperative behavior.
continued here
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